Stanford Advisors

All Publications

  • A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death. bioRxiv : the preprint server for biology Nix, M. N., Gourisankar, S., Sarott, R. C., Dwyer, B. G., Nettles, S. A., Martinez, M. M., Abuzaid, H., Yang, H., Wang, Y., Simanauskaite, J. M., Romero, B. A., Jones, H. M., Krokhotin, A., Lowensohn, T. N., Chen, L., Low, C., Davis, M. M., Fernandez, D., Zhang, T., Green, M. R., Hinshaw, S. M., Gray, N. S., Crabtree, G. R. 2025

    Abstract

    Developing cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provide the structural and molecular underpinnings for an approach that leverages chemical induced proximity to produce specific cell killing of diffuse large B cell lymphoma, the most common non-Hodgkin's lymphoma. We develop KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity) that redirect p300 and CBP to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6. Acute treatment rapidly reprograms the epigenome to initiate apoptosis and repress c-MYC. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance interactions between the two proteins can be systematically exploited to produce the exquisite potency and selectivity of KAT-TCIPs. Thus, the malignant function of an oncogenic driver can be co-opted to activate robust cell death, with implications for precision epigenetic therapies.

    View details for DOI 10.1101/2025.03.14.643404

    View details for PubMedID 40166243

    View details for PubMedCentralID PMC11956963

  • A novel AKR1C3 specific prodrug TH3424 with potent anti-tumor activity in liver cancer. Clinical pharmacology and therapeutics He, P. n., Wang, C. n., Wang, Y. n., Wang, C. n., Zhou, C. n., Cao, D. n., Li, J. n., Bushnell, D. A., Li, Q. n., Kornberg, R. D., Xie, W. n., Wang, Z. n. 2021

    Abstract

    Overexpression of AKR1C3, an aldo-keto reductase, was recently discovered in liver cancers. In this study, an inverse correlation between AKR1C3 expression and liver cancer patient survival was observed. AKR1C3 inhibitors, however, failed to suppress liver cancer cell growth. The prodrug TH3424, which releases a DNA alkylating reagent upon reduction by AKR1C3, was developed to target tumors with overexpression of AKR1C3. TH3424 showed specific killing of liver cancer cells with AKR1C3 overexpression both in vitro and in vivo. In patient-derived mouse xenograft models, TH3424 at doses as low as 1.5 mg/kg eliminated liver tumors with no apparent toxicity. Conclusion: TH3424 is a promising drug candidate for liver cancer and other types of cancers overexpressing AKR1C3.

    View details for DOI 10.1002/cpt.2171

    View details for PubMedID 33483974